The overall objective of this proposal is--in the context of a unique Phase III protocol study designed to determine the clinical effectiveness of trans-retinoic acid (tRA) induction and maintenance therapy vs standard therapy in previously untreated acute promyelocytic leukemia (APL) patients--to define the relevance and/or mechanistic role of certain molecular and cellular elements in determining the level of clinical responsiveness to tRA. Specifically, the following parameters will be tested for possible correlations with clinical-outcome and/or tRA responsiveness of APL cells in vitro: (1) three different forms of the t(15;17)-generated PML-RARalpha fusion gene, only one of which is present in individual APL patients, and/or any of the multiple isoforms of each type of PML-RARalpha mRNA generated by differential splice-joining of exonic sequences; (2) the level of reduction of the leukemic clone, as measured by the APL-specific PML-RARalpha fusion mRNA, after either tRA or chemotherapy-induced remission; (3) the level of expression of the abnormal PML-RARalpha mRNA relative to that of normal PA receptors (RARS), RXRs, cytoplasmic RA binding protein (CRABP), non-chimeric PML and PLZF (a newly cloned PA-responsive gene) in APL cells before and after exposure to tRA; (4) the level of sensitivity of APL cells to tPA-induced differentiation in suspension culture; and (5) the achieved plasma levels of tRA at the initiation and after various periods of therapy with tRA. Correlative analysis of the laboratory data with clinical parameters will be conducted in collaboration with the Statistical Center and Operations Division of the Eastern Cooperative Oncology Group. Laboratory parameters will also be studied at the time of relapse to determine the basis of the frequent development of clinical resistance to tRA. Since RNA availability will be limiting in many cases, polymerase chain reaction (PCR) methodology will be used for most gene expression studies. Detailed pharmacokinetic studies, using high-performance liquid chromatographic methods to measure tRA, will be performed in at least 20 patients.
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